Container for Medicament Powder

ABSTRACT

There is provided a container for a medicament powder formed from a material comprising a desiccant. In one embodiment the container is a medicament dispenser comprising a body defining a reservoir for medicament in powder form, and an outlet in communication with said reservoir. In another embodiment the container is a medicament dispenser comprising a body defining a chamber for receipt of a medicament carrier, and an outlet in communication with said chamber. Methods of controlling moisture flow are also described.

TECHNICAL FIELD

The present invention relates to containers and dispensers formedicament powders. In particular, the invention relates to dry powderinhalation dispensers and components thereof which substantiallyalleviate or reduce moisture build-up therein. The invention alsorelates to a method for reducing moisture ingress inside a dry powderinhaler.

BACKGROUND TO THE INVENTION

Medicaments for treating respiratory disorders are frequentlyadministered as dry powder formulations through the mouth and nose. Drypowder medicament dispensers, such as inhalers, are used in theadministration of these drugs, inhalation by the patient resulting inuptake of a specified dosage of medicament through the nose or mouth.The drug may be stored as a dry powder within a reservoir in the body ofthe inhaler, a metering chamber being utilised to administer a specifieddose of medicament. Alternatively, more sophisticated medicamentdispensers employ medicament carriers, such as individual capsules orblister packs/strips containing defined doses of powdered drug.

Patients often rely on medication delivered by dry powder inhalers forrapid treatment of respiratory disorders that are debilitating and insome cases life threatening. It is, therefore, essential that theprescribed dose of drug is delivered accurately and consistently to meetthe patient's needs and comply with the requirements of regulatoryauthorities.

A problem which can occur in the storage and product lifetime of aninhaler is ingress of moisture into the medicament powder. A build-up ofmoisture can prevent the administration of an effective dose ofmedicament by causing an increase in particle size and/or adherence ofhygroscopic particles to the walls of the carrier or device, therebyleading to reduced uptake via inhalation by the patient. In extremecases, depending upon the chemical nature of the medicament, moisturebuild-up may lead to degradation of the drug.

Another problem can be microbial contamination, which is often assistedby the undesirable presence of excess moisture.

The Applicants have found that the inclusion of a desiccant in the bodyof the inhaler or the walls of the medicament carrier can significantlyimprove the aforementioned problems. Furthermore, storage of the inhaleror medicament carrier within a sealed package incorporating a desiccant,can markedly reduce moisture ingress.

The Applicants has also found that the aforementioned problems can beameliorated by controlling the ingress of moisture to, or egress ofmoisture from, the medicament container. Control may be achieved byeither suitable choice of container materials or by enclosure of thecontainer or a dispenser including the container in a suitable package.The control need not absolutely prevent moisture transfer. Indeed, theApplicants have found that under certain conditions a limited degree ofmoisture transfer can be desirable.

WO 99/32180 teaches the inclusion of moisture permeable chamberscontaining desiccants within a blister pack. U.S. Pat. No. 5,740,793discloses the inclusion of a desiccant cartridge within an inhaler orthe medicament carrier cassette. U.S. Pat. No. 5,394,868 describes achamber within a powder inhaler for holding a desiccating substance. Theuse of desiccant filters within medicament dispensers is described inU.S. Pat. Nos. 5,687,746 and 5,775,320, and PCT patent application no.WO 89/01348.

SUMMARY OF INVENTION

According to the present invention, there is provided a container for amedicament powder formed from a material comprising a desiccant.

In one aspect, the container is suitable for containing a measured doseof medicament. Packs in blister pack form for the containment of a unitdose medicaments are envisaged, as are packs containing multiple unitdose blisters arranged sequentially or otherwise, such as in seriesform. A particular multi-unit dose arrangement comprises an elongatestrip having multiple blisters arranged in series thereon.

In another aspect, the container is a reservoir for dry powdermedicament. Metering means are provided to enable metering of dose fromthe reservoir and transport of that dose to a delivery position.

In one aspect, the container is a medicament dispenser comprising a bodydefining a reservoir for medicament in powder form, and an outlet incommunication with said reservoir for release of the medicament. In oneaspect, the device is an inhaler and the outlet is one through which auser can inhale.

In another aspect, the container is in the form of a reloadablecartridge comprising a medicament pack (e.g. in multi-unit dose blisterform or reservoir form). The cartridge is shaped and sized for receiptby a medicament delivery device (e.g. an inhaler device).

In another aspect, the container is a medicament dispenser comprising abody defining a chamber for receipt of a medicament carrier, and anoutlet in communication with said chamber for release of the medicament.In one aspect, the device is an inhaler and the outlet is one throughwhich the user can inhale.

In yet another aspect, the body consists of the material comprising thedesiccant.

In one aspect, the body comprises the material comprising the desiccant.

In another aspect, the material comprising the desiccant coats the bodye.g. part or whole of the inside of the body.

In yet another aspect, the material comprising the desiccant isimpregnated throughout the body.

In one aspect, the material comprising the desiccant lines the body(e.g. the interior of the body which contacts the medicament powder inuse).

Optionally the desiccant comprising material may be located around aseal for sealing the reservoir or medicament carrier optionally the seal(e.g. in the form of a sealing ring) may itself comprise or consist of adesiccant.

In another aspect, the container is a medicament carrier.

In yet another aspect, the medicament carrier is a capsule comprising awall enclosing the medicament.

In one aspect, the medicament carrier is a blister pack comprising abase sheet and a lid.

In another aspect, the medicament carrier comprises a materialcomprising a desiccant.

In yet another aspect, the material comprising the desiccant coats thewall, or the base sheet, or the lid of the medicament carrier.

In one aspect, the material comprising the desiccant impregnates thewall, or base sheet, or lid of the medicament carrier.

In another aspect, the material comprising the desiccant lines the wall,or base sheet, or lid of the medicament carrier.

In another aspect, the material comprising the desiccant is moulded intothe wall, or base sheet, or lid of the medicament carrier.

In yet another aspect, a well containing desiccant surrounds individualpockets in the blister packs.

In one aspect, the blister pack comprises a laminate comprising adesiccant. Suitably, the laminate comprises material selected from thegroup consisting of metal foil, organic polymeric material and paper.Suitable metal foils include aluminium or tin foil having a thickness offrom 5 to 100 μm, preferably from 10 to 50 μm, such as 20 to 30 μm.Suitable organic polymeric materials include polyethylene,polypropylene, polyvinyl chloride and polyethylene terephthalate.

Suitably, the base sheet and lid comprise different materials.

In another aspect, the material comprising the desiccant is an organicpolymeric plastic having particular characteristics e.g. athermoplastic.

In yet another aspect, the organic polymeric plastic is a polyamide.

Preferably the desiccant is selected from the group consisting of silicagel, zeolite, alumina, bauxite, anhydrous calcium sulphate, activatedbentonite clay, water-absorbing clay, molecular sieve and any mixturesthereof.

In one aspect, the container additionally comprises a medicament in drypowder form. Suitably, the medicament is suitable for the treatment ofrespiratory disorders. Preferably, the medicament is salmeterolxinafoate, fluticasone propionate or a combination thereof.

In another aspect of the present invention there is provided a method ofreducing water ingress into a medicament powder comprising using acontainer for a medicament powder according to any of the precedingclaims.

In another aspect of the present invention there is provided a packagefor storage of a container for a medicament powder formed from amaterial capable of controlling the ingress of moisture thereto oregress or moisture therefrom.

In one aspect, the material is impermeable to moisture.

In another aspect, the material controls the ingress or egress ofmoisture such that the ambient moisture content within the package isessentially constant, such as varying by no more than ±20%, preferablyby less than ±10%. Ambient moisture content may for example be measuredby Relative Humidity within the package. The preferred absolute level ofmoisture content will vary from medicament to medicament but may bereadily determined through laboratory testing.

In another aspect, the material enables moisture transfer in one wayonly i.e. ingress only or egress only.

In another aspect, the material enables moisture transfer to either aset minimum/maximum moisture content within the package or within a setminimum / maximum moisture transfer rate.

In another aspect, the material is also capable of controlling the flowof other gaseous or vapour form species. Tyvek (trade name) is asuitable material.

In one aspect, the package is wrappable and sealable around thecontainer to form an enclosed volume in which the container is disposed,the package being impermeable to water vapour, thereby substantiallyreducing ingress of water vapour and particulate matter into saidenclosed volume.

In another aspect, the package additionally comprises a desiccant withinthe enclosed volume.

Preferably the desiccant is selected from the group consisting of silicagel, zeolite, alumina, bauxite, anhydrous calcium sulphate, activatedbentonite clay, water-absorbing clay, molecular sieve and any mixturesthereof.

In one aspect the package includes at least one heat sealable layer andat least one layer of a metal foil.

In another aspect, the metal comprising said metal foil is selected fromthe group consisting of aluminium, tin, iron, zinc and magnesium.

In yet another aspect, the package includes protective layers located onthe outside of the package.

In one aspect, the protective layer comprises a polyester film and theheat sealable layer comprises an ionomer film.

In another aspect of the present invention there is provided a method ofstoring a container for a medicament powder comprising providing apackaging material which is capable of controlling the flow of watervapour; filling a container with a medicament powder; wrapping saidcontainer with said package material to form an enclosed volume in whichsaid container is disposed therein; and sealing the package.

In yet another aspect, the method additionally comprises providing adesiccant within the enclosed volume.

In one aspect, the sealing comprises heat sealing said packagingmaterial. In other aspects, the seal is formed by ultrasonic welding,heat stamping, adhesive or laser welding methods.

In another aspect of the present invention there is provided a packagedcontainer, comprising a container containing a medicament powder; and anoverwrap package enclosing the container and a desiccant; wherein thecontainer and the desiccant are sealable within the overwrap. Preferablythe overwrap comprises a desiccant material and/or is lined, coated orimpregnated with a desiccant material.

The overwrap package may be in the form of a shrink wrap or of a loosewrap e.g. in sachet form. Any spare volume within the overwrap may beevacuated or an inert gas such as nitrogen deliberately inserted.

In another aspect of the present invention there is provided a packagedpowder medicament dispenser (or reloadable cartridge therefor asdescribed supra) comprising a medicament dispenser for a medicamentpowder; and an overwrap package enclosing the medicament dispenser,wherein the medicament dispenser are sealable within the overwrap. Theoverwrap package may comprise desiccant, and or the package may havedesiccant contained therewithin. The medicament dispenser may comprise apowder reservoir or a medicament carrier for containment of medicament.

Where the overwrap comprises desiccant it may be impregnated orotherwise blended with material or added as a coating or a liner.

In another aspect, the body of said medicament dispenser also comprisesa desiccant.

Preferably the desiccant is selected from the group consisting of silicagel, zeolite, alumina, bauxite, anhydrous calcium sulphate, activatedbentonite clay, water-absorbing clay, molecular sieve, zinc chloride,and any mixtures thereof.

In another aspect of the present invention there is provided a containerfor a medicament powder formed from a material capable of controllingthe ingress of moisture thereto or egress or moisture therefrom.

In one aspect, the material is impermeable to moisture.

In another aspect, the material controls the ingress or egress ofmoisture such that the ambient moisture content within the package isessentially constant, such as varying by no more than ±20%, preferablyby less than ±10%.

In another aspect, the material enables moisture transfer in one wayonly i.e. ingress only or egress only.

In another aspect, the material enables moisture transfer to either aset minimum/maximum moisture content within the package or within a setminimum/maximum moisture transfer rate.

In another aspect, the material is also capable of controlling the flowof other gaseous or vapour form species.

In other aspects, the medicament container or overwrap therefor or anypart of a medicament dispenser for use therewith is comprised of amaterial having desiccant blended or otherwise loaded or impregnatedtherein. Suitable materials are described in PCT Application Nos.WO99/62697 and WO/00/17258 in the name of Capitol Speciality PlasticsInc.

Suitable materials comprise a thermoplastic/desiccant blend. Examples ofthermoplastics include polyolefin, polyethylene, polycarbonate,polyamide, ethylene-vinyl acetate copolymer, ethylene-methacrylatecopolymer, polyvinyl chloride, polystyrene, polyester, polyester amide,polyacrylic ester, and polyvinylidene chloride, acrylic, polyurethane,polyacetal, and polycarbonate. These and other thermoplastics may beutilized either singularly, or in combinations.

The concentration of desiccant entrained (e.g. mixed or blended) withinthe thermoplastic may exceed seventy-five percent (75%) to not greaterthan eighty percent (80%) by weight, so that about seventy-five percent(75%) may extend to eighty percent (80%) by weight. Typically, however,the desiccant concentration will fall within a range of forty toseventy-five percent (40-75%) desiccant to thermoplastic, by weight.This concentration is considered to be a high concentration for mostthermoplastics. The maximum desiccant bearable concentrations will varyamong the various types of thermoplastics due to their differingcharacteristics. In the instance of polyethylene or polypropylene, forexample, the maximum concentration of desiccant will be aboutseventy-five percent (75%) by weight. As the desiccant concentrationswithin the thermoplastics increase, the performance of the materialdegenerates to unacceptable levels. At lower levels of desiccantconcentrations, about forty percent (40%) could extend to as low asthirty percent (30%) where the limits of a viable product are reached.

BRIEF DESCRIPTION OF INVENTION

FIG. 1 shows a medicament carrier in the form of a capsule according tothe present invention.

FIG. 2 a is a cross-sectional side elevation of a single medicamentblister strip impregnated with a desiccant according to the presentinvention.

FIG. 2 b is a top perspective of a medicament blister strip illustratedin FIG. 2 a.

FIG. 3 a is a cross-sectional side elevation of a single medicamentblister having a laminate comprising a desiccant according to thepresent invention.

FIG. 3 b is a top perspective of a medicament blister strip illustratedin FIG. 3 a.

FIG. 4 a is a cross-sectional side elevation of a single medicamentblister having a ring containing a desiccant impregnated into thelaminate surrounding the blister pocket.

FIG. 4 b is a top perspective of the medicament blister shown in FIG. 4a.

FIG. 5 shows a cross-sectional dry powder inhaler comprising a powderreservoir according the present invention.

FIG. 6 shows a cross-sectional dry powder inhaler comprising amedicament carrier according to the present invention.

FIG. 7 is a top perspective of a package for storing a dry powderinhaler according to the present invention.

FIG. 8 is a side perspective of the package of FIG. 7.

FIG. 9 is a cut-away bottom perspective of the package for storing a drypowder inhaler according to the present invention.

FIG. 10 is a cross-sectional view of the package for storing a drypowder inhaler according to the present invention.

DETAILED DESCRIPTION OF THE DRAWINGS

The medicament carrier in FIG. 1 is in the form of a capsule 1comprising a wall 2 enclosing medicament powder 5. The wall 2 comprisesa desiccant 3 which reduces or otherwise controls moisture ingress intothe capsule 1 during storage and/or when in situ within the body of theinhaler (not shown). Medicament powder 5 is released on piercing thewall 2 of capsule 1 and may be inhaled by a patient.

FIG. 2 a shows a sectional side-elevation of a single blister strip 106comprising a pocket 107, containing dry powder 105, base 110 and lidcomprising laminates 114, 115. The lid is composed of a metallic foillaminate 114 bound to a plastic laminate 115. In the diagram, the lid114, 115 is hermetically sealed to base 110 by appropriate means (e.g.adhesion, welding). Base 110 comprises an organic polymeric plasticimpregnated with desiccant 103. In use, the desiccant absorbs anymoisture which permeates through the lid 114, 115 and base 110,maintaining the powder 105 in a dry condition until the lid 114, 115 isremoved from the base 110.

A top perspective of the blister strip 106 showing pockets 107 isillustrated in FIG. 2 b. Laminated lid 114, 115 is sealed to base 110which is impregnated with desiccant 103.

FIG. 3 a shows a cross-sectional elevation of a different single blisterstrip 206 according to the invention. The blister strip 206 is composedof several laminated sheets, the lid being formed from metallic foil 214and plastic laminate 215 while the base comprises plastic laminates 210and 211. The plastic laminate 211 comprises a desiccant material 203 forabsorbing any moisture which permeates through laminated sheets 214, 215and 210, thereby reducing ingress into medicament powder 205 withinpocket 207.

FIG. 3 b is a top perspective of a blister strip 206 showing severalblisters as described in FIG. 3 a. Metallic foil 214 and plasticlaminate 215 form a lid which is hermetically sealed, by appropriateadhesive or welding means, to the base of strip 206. The base comprisesplastic laminates 210 and 211, laminate 211 being disposed on theinternal surface of pocket 207 and comprising a desiccant.

FIG. 4 a shows a cross-sectional elevation of yet another single blisterstrip 306 according to the invention. Metallic foil 314 and plasticlaminate 315 form a lid for base 310 which are hermetically sealedtogether to reduce moisture ingress into pocket 307 containingmedicament powder 305. The circumference of pocket 307 is surrounded bya ring 319, within base 310, comprising desiccant 303 which absorbsmoisture which permeates into the blister, particularly between lidsheet 315 and base sheet 310.

A plan perspective of the single blister strip 314 shown in FIG. 4 a isillustrated in FIG. 4 b. The ring 319 of material comprising desiccant303 surrounds pocket 307 thereby absorbing any moisture which permeatesinto the pocket 307 through foil 314 and laminates 315 and/or base sheet310, together with moisture ingress between lid and base sheets 315,310.

FIG. 5 shows a sectional view of a dry powder inhaler 420 according tothe present invention. The inhaler 420 comprises a body 421 whichdefines a reservoir 423 and a reservoir cover 424. The reservoircontains a supply of medicament in dry powder form 405. The walls 423 ofthe reservoir, defined by the body 421, are comprised of a desiccantmaterial 403. Base 425 and body 421 define an aperture 430 through whichpowder 405 can pass from the reservoir to the dosing member 432. Powder405 is guided by the walls 423 of the reservoir, which form a hopper, tothe dosing member 432. Extending laterally from the lower end of themain body 421 is mouthpiece 435, through which the patient inhales viapassage 433. If the device were intended for nasal inhalation this wouldbe replaced by a nosepiece. The desiccant material 403, comprising walls423, reduce moisture absorption by medicament powder 405. Optionally adesiccant comprising material may be located within the walls of passage433 and/or a ring of same material around the metering valve (not shown)which controls the flow of medicament into passage 433.

FIG. 6 shows a simplified cross-sectional plan view of a dry powderinhaler comprising a medicament carrier according to the presentinvention. The inhaler 540 dispenses unit doses of medicament powderfrom a medicament blister strip 506. The inhaler is comprised of anouter casing 544 enclosing a medicament strip 506 within body 521. Themedicament strip may be, for example, any of those described in FIGS. 2a to 4 b above. The internal walls of body 521 are comprised of adesiccant material (not shown) which reduce the levels of moisturewithin the internal cavity of the inhaler, thereby protecting themedicament powder within strip 506. The patient uses the inhaler byholding the device to his mouth, depressing lever 538, and inhalingthrough mouthpiece 535. Depression of lever 538 activates the internalmechanism of the inhaler, such that the lid 514 and base 510 sheets ofcoiled medicament blister strip 506 are separated at index wheel 541 byuse of contracting wheel 542 and base wheel 543. A unit dose of powderedmedicament within blister pocket 507 is released and may be inhaled bythe patient through exit port 533 and mouthpiece 535.

FIG. 7 shows a top perspective of a container storage system for storinga dry powder inhaler or cartridge refill therefor according to thepresent invention. The container storage system 650 includes a packageor wrapping 652 that employs multi-layers of material 970, 972, 974.(See FIG. 10.) The package 652 further includes fin seams 654, 656 whichare disposed along two parallel side edges of the package and along asingle longitudinal edge of the package 652. The package 652 comprises adesiccant material, or alternatively is lined, coated or impregnatedwith a desiccant material.

The number and type of fin seams 654, 656 are not limited to the typesshown in the drawings. The package 652 can include additional seams orsignificantly fewer seams such as a continuous single seam. Theorientation of the seams 654, 656 is not limited to the orientationshown in the drawings. The orientation of the seams 654, 656 istypically a function of the sealing device and such seams may beoriented in a manner which substantially increases manufacturingefficiency. During manufacture, the longitudinal seam 654 may be formedfirst by heat sealing and the two end seams 656 may then be formed byheat sealing to close the package. Other types of seams include, but arenot limited to, gusset type seams which include excess material whichprovides expansibility, stitched type seams, or mechanically crimpedseams, and other like structures.

The container storage system includes a dry powder inhaler 820 (see FIG.9). While the preferred inhaler is a dry powder inhaler 820, other drypowder inhalers (such as that described in FIG. 6) are not beyond thescope of the present invention.

FIG. 8 shows a side perspective of the container storage system of FIG.7. The fin seams 654 and 656 in FIG. 7 are formed by a conventional heatsealing device which mechanically crimps sides of the package 750together while simultaneously providing heat to the sides 654, 656/756(FIGS. 7 and 8). The heat sealing device typically has electrical heaterelements shaped to produce the pattern of the fin seams 654, 656/756where the fin seams include multiple ridges 658/758. The sealingmechanism of the container storage system 650/750 of the presentinvention is not limited to heat sealing devices. Other sealing devicesinclude, but are not limited to, glue sealing machines, sonic weldingmachines, electron beam radiation machines, and other like sealingdevices.

As shown in FIG. 7, the package 750 preferably has a substantiallyrectangular configuration with a substantially elliptical cross section,however, other shapes of the package 750 are not beyond the scope of thepresent invention. Other shapes include, but are not limited tocircular, square, triangular, trapezoidal, pentagonal, hexagonal,octagonal, and other like shapes. The shape of the package 750 ispreferably a function of the shape of the enclosed medicament powdercontainer 34 as well as the amount and type of storage space since thepackage 752 is made from flexible materials as will be described infurther detail below.

FIG. 9 shows a cut-away bottom perspective of the package for storing adry powder inhaler according to the present invention. The package 852provides an enclosed volume 860 in which the inhaler 820 is disposedtherein. The size of the enclosed volume 860 can be adjusted accordingto the size of the inhaler 820 and related parts thereto. Preferably,the enclosed volume 860 is of a size which permits relative ease ofclosing respective sides and layers 852, 26 and 28 without substantialstretching of the package 852. The enclosed volume 860 may besubstantially evacuated prior to formation of the fin seams 858, 854(not shown) to substantially reduce any water vapour being present inthe enclosed volume 860. The enclosed volume 860 may be evacuated tosuch a degree that the enclosed volume 860 is a vacuum region around themedicament inhaler 820. While the enclosed volume 860, may remainconstant, its relative shape may change according to shifting of theinhaler 820 disposed within the enclosed volume 860. In a preferredembodiment, a porous container of moisture absorbing material 862 laysadjacent to the mouthpiece 835 in a loose or free flowing manner.Alternatively, the moisture absorbing material 862 can be secured to theinside of the flexible package. In another alternative embodiment, themoisture absorbing container 862 may be attached to a bracket structuresuch as a ring which is fastened to the inhaler 820.

In one possible embodiment, the moisture absorbing material may beattached to the external surface of the mouthpiece 835 by a fasteningdevice such as a rubber band 863. The fastening device 863 is preferablya removable elastic mechanism such as a rubber band. However, otherfastening devices are not beyond the scope of the present invention.Other fastening devices include, but are not limited to, adhesives,adhesive tapes, shrink-wrap plastic, fasteners such as screws, nails, orrivets, compartments which are part of the mouthpiece housing 46, andother like attachment devices. In an alternative embodiment (not shown),a plurality of beads of material comprising a desiccant may be placedwithin the enclosed space 860. Similarly, other carriers comprised of adesiccant material may be enclosed within space 860 to absorb excessmoisture from the enclosure.

FIG. 10 is a cross-sectional view of the package for storing a drypowder inhaler according to the present invention. The amorphous shapeof the enclosed volume 960 is attributed to the flexible materials whichmake up the layers 970, 972, 974 of the package 952. The enclosed volume960 can be varied in size such that it substantially conforms to theshape of the inhaler and any related parts thereto or such that theenclosed volume 960 is larger than the inhaler 820, as shown in FIG. 9.When the enclosed volume is of a size which is substantially equivalentwith the surface area of the inhaler 820 and related parts, the layers970, 972, and 974 of material substantially conform to the shape of theinhaler and related parts. The package is preferably placed in aseparate, more rigid container, such as a paperboard or cardboard box(not shown) typically used in the pharmaceutical industry. The packagemay expand during storage due to slow leakage of volatiles from theplastics constituting the body of the inhaler. In this situation, theshape of the package may conform to some extent to the internal shape ofthe rigid container if the volume of the rigid container is justslightly larger than the expanded volume of the flexible package.

Flexible Packaging Materials

The flexible packaging material can be any material which is imperviousto or substantially impervious to moisture. The packaging material ispreferably permeable to volatiles which may escape from the plasticsforming the body of the inhaler and/or the medicament carrier, bydiffusion or otherwise, thereby preventing a build-up in pressure.

For ease of manufacturing, and in order to provide the necessaryproperties to the packaging material, the flexible packaging materialpreferably comprises a non-thermoplastic substrate (such as a metalfoil) and a heat sealable layer disposed thereon, and an additionalprotective layer, such as a polymer film of polyester. The heat sealablelayer is usually disposed on the inner surface of the assembled package.The additional protective layer is usually disposed on the surfaceopposite the heat sealable layer. An example of a particularly usefulfoil laminate is a polyester film adhesively laminated to aluminium foiladhesively laminated to Ionomer (SURLYN™) film, for example, 12μpolyester/9μ aluminum/50μ ionomer film supplied by Lawson Mardon Singen(LMS). To further reduce moisture ingress, thicker metal films, such as20 to 25μ, may be used.

The substrate is preferably formed from aluminium foil. However, othermetals for the substrate include, but are not limited to, tin, iron,zinc, or magnesium formed on a sheet by vacuum deposition or sputteringand a carboxyl group-containing polyolefin layer formed on the metallayer by lamination.

The heat sealable layer can be formed from any thermoplastic orthermosetting material such as an ionomer resin, polyolefin, orcycloolefin copolymer. Ionomer resins typically include ionicallycross-linked ethylene-methacrylic acid and ethylene acrylic acidcopolymers. Properties which distinguish these ionomers resins fromother polyolefin heat-sealed polymers are high clarity, high impactresistance, low haze in lamination, tear resistance, abrasionresistance, solid state toughness, and moisture imperviousness. In thepreferred embodiment, the heat sealable layer is made out of SURLYN™ (anionomer resin) or a form of polyethylene to provide sufficient heatsealing properties.

The outer protective layer, if present, can be formed of any material aslong as the final laminate has the requisite properties.

Preferably, the protective layer (e.g., polyester) is adhesivelylaminated to the substrate (e.g., aluminium) and the substrate layer inturn is adhesively laminated to the heat sealable layer (e.g., theionomer film or SURLYN™ (an ionomer resin)). Preferred exemplarythicknesses of the three layers include a protective layer 1 to 40,preferably 4 to 30, more preferably 10 to 23 microns, and mostpreferably 12 microns; a substrate layer of 1 to 100, preferably 3 to70, more preferably 5 to 50 microns, more preferably 6 to 20 microns,and most preferably 9 microns. For the heat sealable layer, preferredexemplary thicknesses include thicknesses of 1 to 100, preferably 5 to70, more preferably 10 to 60, more preferably 20 to 55 microns, and mostpreferably 50 microns.

Adhesives may be used to join the respective layers of materialstogether. The adhesive layers are typically substantially smaller inthickness relative to the thickness of the substrate, heat sealableand/or protective layers which they bond. The number, size, and shape ofthe layers are not limited to those layers shown in the drawings. Anynumber of layers with relative areas of any size and predeterminedthicknesses may be used so long as the flexible package forms anenclosed volume which substantially prevents ingression of water vapourand particulate matter into the enclosed volume while permittingegression out of the enclosed volume of any volatile released from theplastics used in the body of the inhaler or the medicament carrier. Thesize, shape, and number of layers of the package are typically afunction of the size and contents of the inhaler and/or medicamentcarrier.

The package is believed to operate similarly to a virtual one-way valvedue to the composition of the layers and due to the transmission rate ofwater vapour molecules into the enclosed volume relative to thetransmission rate of gas molecules of a plastic volatile, such asformaldehyde, out of the enclosed volume. The package permits thevolatile to diffuse out of the enclosed volume while substantiallypreventing water vapour and other particulate matter from entering theenclosed volume. Excess or leakage of the volatile is permitted toegress from the package. The virtual one-way valve function of thepackage prevents or minimizes the chance of any sudden ruptures orprevents or minimizes unexpected expulsion of the plastic volatileduring opening of the package.

Moisture Absorbing Materials

The moisture absorbing material is preferably a silica gel desiccantsachet. However, other vapour or moisture absorbing mechanisms are notbeyond the scope of the present invention. Other vapour or moistureabsorbing materials include desiccants made from inorganic materialssuch a zeolites and aluminas. Such inorganic materials of vapour ormoisture absorbing materials have high water absorption capacities andfavourable water absorption isotherm shapes. The water absorptioncapacity of such materials typically varies from 20 to 50 weightpercent. In the preferred embodiment, the absorbing material is aMINIPAX® supplied by Multisorb Technologies in the United States andSilgelac in Europe (silica gel packaged inside TYVEK®, which is a nylonmesh bonded with a microporous polyurethane). Other exemplary moistureabsorbing materials include, but are not limited to, alumina, bauxite,anhydrous, calcium sulphate, water-absorbing clay, activated bentoniteclay, a molecular sieve, or other like materials which optionallyinclude a moisture sensitive colour indicator such as cobalt chloride toindicate when the desiccant is no longer operable. While in thepreferred embodiment of the present invention, the package is designedto substantially prevent ingression of water vapour and particulatematter into the enclosed volume, the moisture absorbing material isplaced within the enclosed volume in order to absorb any residualmoisture present in the atmosphere or on the external surface of thepressurized container or mouthpiece or a combination thereof, prior tosealing the package.

The desiccant should be present in an amount sufficient to absorb anyresidual moisture inside the package. When silica gel is used, 1 g to 10g of silica gel is sufficient for a typical dry powder inhaler.Moreover, the desiccant should be present in an amount sufficient toabsorb any moisture that possibly ingresses from the externalenvironment. It is also possible to place the desiccant inside thecontainer, either loose in the canister or as part of an assemblyattached to the canister.

Medicaments

Appropriate medicaments may thus be selected from, for example,analgesics, e.g., codeine, dihydromorphine, ergotamine, fentanyl ormorphine; anginal preparations, e.g., diltiazem; antiallergics, e.g.,cromoglycate (eg s the sodium salt), ketotifen or nedocromil (eg as thesodium salt); antiinfectives e.g., cephalosporins, penicillins,streptomycin, sulphonamides, tetracyclines and pentamidine;antihistamines, e.g., methapyrilene; anti-inflammatories, e.g.,beclomethasone (eg as the dipropionate ester), fluticasone (eg as thepropionate ester), flunisolide, budesonide, rofleponide, mometasone egas the furoate ester), ciclesonide, triamcinolone (eg as the acetonide)or6α,9α-difluoro-11β-hydroxy-16α-methyl-3-oxo-17α-propionyloxy-androsta-1,4-diene-17β-carbothioicacid S-(2-oxo-tetrahydro-furan-3-yl) ester; antitussives, e.g.,noscapine; bronchodilators, e.g., albuterol (eg as free base orsulphate), salmeterol (eg as xinafoate), ephedrine, adrenaline,fenoterol (eg as hydrobromide), formoterol (eg as fumarate),isoprenaline, metaproterenol, phenylephrine, phenylpropanolamine,pirbuterol (eg as acetate), reproterol (eg as hydrochloride), rimiterol,terbutaline (eg as sulphate), isoetharine, tulobuterol or4-hydroxy-7-[2-[[2-[[3-(2-phenylethoxy)propyl]sulfonyl]ethyl]amino]ethyl-2(3H)-benzothiazolone;adenosine 2a agonists, eg2R,3R,4S,5R)-2-[6-Amino-2-(1S-hydroxymethyl-2-phenyl-ethylamino)-purin-9-yl]-5-(2-ethyl-2H-tetrazol-5-yl)-tetrahydro-furan-3,4-diol(e.g. as maleate); α₄ integrin inhibitors eg(2S)-3-[4-({[4-(aminocarbonyl)-1-piperidinyl]carbonyl}oxy)phenyl]-2-[((2S)-4-methyl-2-{[2-(2-methylphenoxy)acetyl]amino}pentanoyl)amino]propanoic acid (e.g as free acid or potassium salt), diuretics, e.g.,amiloride; anticholinergics, e.g., ipratropium (eg as bromide),tiotropium, atropine or oxitropium; hormones, e.g., cortisone,hydrocortisone or prednisolone; xanthines, e.g., aminophylline, cholinetheophyllinate, lysine theophyllinate or theophylline; therapeuticproteins and peptides, e.g., insulin or glucagon; vaccines, diagnostics,and gene therapies. It will be clear to a person skilled in the artthat, where appropriate, the medicaments may be used in the form ofsalts, (e.g., as alkali metal or amine salts or as acid addition salts)or as esters (e.g., lower alkyl esters) or as solvates (e.g., hydrates)to optimise the activity and/or stability of the medicament.

Preferred medicaments are selected from albuterol, salmeterol,fluticasone propionate and beclomethasone dipropionate and salts orsolvates thereof, e.g., the sulphate of albuterol and the xinafoate ofsalmeterol.

Medicaments can also be delivered in combinations. Preferredformulations containing combinations of active ingredients containsalbutamol (e.g., as the free base or the sulphate salt) or salmeterol(e.g., as the xinafoate salt) or formoterol (eg as the fumarate salt) incombination with an antiinflammatory steroid such as a beclomethasoneester (e.g., the dipropionate) or a fluticasone ester (e.g., thepropionate) or budesonide. A particularly preferred combination is acombination of fluticasone propionate and salmeterol, or a salt thereof(particularly the xinafoate salt). A further combination of particularinterest is budesonide and formoterol (e.g. as the fumarate salt).

It may be appreciated that any of the parts of the medicament containerused therewith which contact the medicament may be coated with materialssuch as fluoropolymer materials which reduce the tendency of medicamentto adhere thereto. Suitable fluoropolymers includepolytetrafluoroethylene (PTFE) and fluoroethylene propylene (FEP). Anymovable parts may also have coatings applied thereto which enhance theirdesired movement characteristics. Frictional coatings may therefore beapplied to enhance frictional contact and lubricants used to reducefrictional contact as necessary.

It will be understood that the present disclosure is for the purpose ofillustration only and the invention extends to modifications, variationsand improvements thereto.

The application of which this description and claims form part may beused as a basis for priority in respect of any subsequent application.The claims of such subsequent application may be directed to any featureor combination of features described therein. They may take the form ofproduct, method or use claims and may include, by way of example andwithout limitation, one or more of the following claims:

1.-26. (canceled)
 27. A package for storage of a container for amedicament powder formed from a material capable of controlling theingress of moisture thereto or egress of moisture therefrom such thatthe moisture content within the package is essentially constant. 28.(canceled)
 29. A package according to claim 27, wherein the materialenables moisture transfer in one way only.
 30. A package according toclaim 27, wherein the material enables moisture transfer to a setmaximum or minimum level within the package.
 31. A package according toclaim 27, wherein the material enables moisture transfer within a setmaximum or minimum transfer rate.
 32. A package according to claim 27,wherein said package is wrappable and sealable around the container toform an enclosed volume in which the container is disposed, therebycontrolling ingress or egress of moisture.
 33. A package according toclaim 32, additionally comprising a desiccant within the enclosedvolume.
 34. A package according to claim 33, wherein said desiccant isselected from the group consisting of silica gel, zeolite, alumina,bauxite, anhydrous calcium sulphate, activated bentonite clay,water-absorbing clay, molecular sieve and any mixtures thereof.
 35. Apackage according to claim 27 wherein the package includes at least oneheat sealable layer and at least one layer of a metal foil.
 36. Apackage according to claim 35, wherein the metal comprising said metalfoil is selected from the group consisting of aluminium, tin, iron, zincand magnesium.
 37. A package according to claim 36, wherein the packageincludes protective layers located on the outside of the package.
 38. Apackage according to claim 37, wherein said protective layer comprises apolyester film and said heat sealable layer comprises an ionomer film.39. A method of storing a container for a medicament powder comprisingproviding a packaging material; filling a container with a medicamentpowder; wrapping said container with said package material to form anenclosed volume in which said container is disposed therein; and sealingthe package, characterized in that said packaging material is capable ofcontrolling the ingress of moisture to or egress of moisture from saidenclosed volume such that the moisture content within the package isessentially constant.
 40. A method of storing a container for amedicament powder according to claim 39, additionally comprisingproviding a desiccant within the enclosed volume.
 41. A method accordingto claim 39, wherein said sealing comprises sealing said packagingmaterial using a method selected from the group consisting of heatsealing, ultrasonic welding, laser welding, adhesive sealing and heatstamping. 42-46. (canceled)
 47. A container for a medicament powderformed from a material capable of controlling the ingress of moisturethereto or egress of moisture therefrom such that the moisture contentwithin the package is essentially constant.
 48. (canceled)
 49. Acontainer according to claim 47, wherein the material enables moisturetransfer in one way only.
 50. A container according to claim 47, whereinthe material enables moisture transfer to a set maximum or minimum levelwithin the package.
 51. A container according to claim 47, wherein thematerial enables moisture transfer within a set maximum or minimumtransfer rate.